Acne Vulgaris is a common skin disorder that affects 80% of the population, typically teenagers and young adults. Over 50 million people in the US are affected by acne generating a $2 billion market for acne treatments, 80% of which is derived from prescription medications. Although acne is not a life threatening condition, it still has a hih psychosocial impact resulting in depression, anxiety, anger, suicidal thoughts, physical scarring and decreased quality of life. The primary causes of acne are the overproduction of sebum by sebaceous glands, hyperkeratinization of follicular epithelium, P. acnes proliferation and inflammation. Unfortunately, the molecular mechanisms of sebum regulation are not clearly understood and this has impeded the generation of safe and effective sebosuppressive therapeutics. Retinoids have been used for more than 20 years to treat severe acne and are the only approved therapy that is effective against multiple pathological processes of acne. However, because of serious concerns regarding the teratogenic properties of retinoids, their use is now part of an FDA-mandated registry program. In addition, isotretinoin has been linked to serious side effects including clinical depression, inflammatory bowel disease and sensitive skin. There is a clear need for safe and efficacious treatments that target sebum production in sebocytes. We have identified a novel compound class in a phenotypic screen for peroxisome biogenesis that inhibits sebocyte lipid biosynthesis. Initial SAR studies surrounding this parental compound are promising and justify screening the additional derivatives to establish proof-of-concept for these compounds as acne therapeutics. The aims of this phase I project are to use our existing cell-based human sebocyte screening platform, ex-vivo skin models and in vivo Syrian hamster model to identify lead compounds in this class for further development in Phase II studies.